1. Field of the Invention
The present invention is directed to providing, preparing and using compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to selecting and preparing compounds which inhibit the enzyme cytochrome P450RAI, many of which are derivatives of phenylacetic or heteroarylacetic acid, and using said compounds for treatment of diseases and conditions which are normally treated by retinoids.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
Several compounds having retinoid-like activity are actually marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural product, biosynthesized and present in a multitude of human and mammalian tissues and is known to play an important rule in the regulation of gene expression, tissue differentiation and other important biological processes in mammals including humans. Relatively recently it has been discovered that a catabolic pathway in mammals, including humans, of natural retinoic acid includes a step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoic acid inducible).
Several inhibitors of CP450RAI have been synthesized or discovered in the prior art, among the most important ones ketoconazole, liarozole and R116010 are mentioned. The chemical structures of these prior art compounds are provided below. It has also been noted in the prior art, that administration to mammals, including humans, of certain inhibitors of CP-450RAI results in significant increase in endogeneous RA levels, and further that treatment with CP450RAI inhibitors, for example with liarozole, gives rise to effects similar to treatment by retinoids, for example amelioration of psoriasis. 
The following publications describe or relate to the above-summarized role of CP450RAI in the natural catabolism of RA, to inhibitors of CP-450RAI and to in vitro and in vivo experiments which demonstrate that inhibition of CP450RAI activity results in a increases endogeneous RA levels and potential therapeutic benefits:
Kuijpers, et al., xe2x80x9cThe effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretinxe2x80x9d, British Journal of Dermatology, (1998) 139: pp 380-389.
Kang, et al., xe2x80x9cLiarozole Inhibits Human Epidermal Retinoid Acid 4-Hydroxylase Activity and Differentially Augments Human Skin Responses to Retinoic Acid and Retinol In Vivoxe2x80x9d, The Journal of Investigative Dermatology, (August 1996) Vol. 107, No. 2: pp 183-187.
Van Wauwe, et al., xe2x80x9cLiarozole, an Inhibitor of Retinoic Acid Metabolism, Exerts Retinoid-Mimetic Effects in Vivoxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2: pp 773-779.
De Porre, et al., xe2x80x9cSecond Generation Retinoic Acid Metabolism Blocking Agent (Ramba) R116010: Dose Finding in Healthy Male Volunteersxe2x80x9d, University of Leuven, Belgium, pp 30.
Wauwe, et al., xe2x80x9cKetoconazole Inhibits the in Vitro and in Vivo Metabolism of All-Trans-Retinoic Acidxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.
White, et al., xe2x80x9ccDNA Cloning of Human Retinoic Acid-metabolizing Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*xe2x80x9d, The Journal of Biological Chemistry, (1997) Vol. 272, No. 30, Issue of July 25 pp 18538-18541.
Hanzlik, et al., xe2x80x9cCyclopropylamines as Suicide Substrates for Cytochromes P450RAIxe2x80x9d, Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-761.
Ortiz de Montellano, xe2x80x9cTopics in Biologyxe2x80x94The Inactivation of Cytochrome P450RAIxe2x80x9d, Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 201-210.
Hanzlik, et al. xe2x80x9cSuicidal Inactivation of Cytochrome P450RAI by Cyclopropylamines greater than  Evidence for Cation-Radical Intermediatesxe2x80x9d, J. Am. Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052.
In accordance with the present invention several previously known and several new compounds are utilized as inhibitors of CP450RAI to provide therapeutic benefit in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids and or which in healthy mammals, including humans, are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the enzyme CP450RAI that catabolyzes natural RA, endogenous RA level is elevated to a level where desired therapeutic benefits are attained. The chemical structures of certain previously known compounds which have been discovered to be inhibitors of the enzyme CP450RAI are provided in the descriptive portion of this application for patent. The chemical structures of the novel compounds which are used in the methods of treatment in accordance with the invention are summarized by Formulas 1 through 8 in the Summary Section of this application for patent. Based on these chemical structures the following art is of interest as background to the novel structures.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658; 5,130,335; 4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP0 130,795; DE 3316932; DE 3708060; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 1.
U.S. Pat. Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 4,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP 0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press Inc., 1990, pages 324-356; are of interest to compounds of Formula 2.
Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; is of interest to compounds of Formula 3.
U.S. Pat. Nos. 5,965,606; 5,773,594; 5,675,024; 5,663,347; 5,023,341; 5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519; 4,826,969; 4,833,240; 5,037,825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP0 098 591; EP0 170 105; EP0 176 034; EP0 253,302; EP0 303 915; EP0 514 269; EP0 617 020; EP0 619 116; EP0 661 259; DE 3316932; DE 3602473; DE 3715955; UK application GB 2190378; Eyrolles et al., J. Med. Chem., (1994), 37, 1508-1517; Graupner et al. Biochem. and Biophysical Research Communications, (1991), 1554-1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 5.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwert JP6072866; Dawson, et al xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 6.
U.S. Pat. Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341; 5,739,338; 5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 5,037,825; EP0 130 795; DE 3316932; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 7.
U.S. Pat. Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154; 4,740,519; 4,826,969; 4,826,984; 4,833,240; 5,037,825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP0 098 591; EP0 130 795; EP0 176 034; EP0 253 302; EP0 303 915; EP0 514 269; EP0 617 020; EP0 619 116; EP0 661 259; DE 3316932; DE 3602473; DE 3708060; DE 3715955; U.K. application GB 2190378; Eyrolles et al., J. Med. Chem., (1994), 37 1508, 1517; Graupner et al., Biochem. and Biophysical Research Communications, (1991) 1554-1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et aL xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 8.
Prior art which is of interest as background to the previously known compounds that have been discovered in accordance with the present invention to be inhibitors of cytochrome P450RAI, is identified together with the identification of these known compounds.
In accordance with the present invention novel compounds of Formulas 1 through 8 are used as inhibitors of the enzyme cytochrome P450RAI to treat diseases and conditions which are normally responsible to treatment by retinoids, or which are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism""s naturally occurring retinoic acid. These novel compounds are shown by Formulas 1 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94;
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 2;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 2 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 4;
R5 is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 4 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X1 is 1-imidazolyl, or lower alkyl or halogen substituted 1-imidazolyl, OR, SR, NRR6 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
R6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that when Y is H, A is phenyl and X1 is OH then n is 1 to 4.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 5 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C1-6-trialkylsilyl or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons;
n is an integer having the values of 1 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 6 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR7, SR7 or NRR7 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons or C1-6-trialkylsilyl.
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 7 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 8 
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X3 is S, or O, C(R1)2, or CO;
Y1 is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of:
Y1 is cycloalkyl,
when Y1 is not cycloalkyl then X3 is O or S and n is 1,
when Y1 is not cycloalkyl then X3 is CO, and n is 1,
when Y1 is not cycloalkyl then X3 is CO and the moiety A is substituted with at least one F group.
In accordance with the invention the novel compounds of Formula 1 through Formula 8 as well as the previously known compounds disclosed below in the specification are used for the prevention or treatment of diseases and conditions in mammals, including humans, those diseases or conditions that are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism""s naturally occurring retinoic acid. Because the compounds act as inhibitors of the breakdown of retinoic acid, the invention also relates to the use of the compounds of Formula 1 through Formula 8 in conjunction with retinoic acid or other retinoids. In this regard it is noted that retionoids are useful for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The retinoids are also useful for the prevention and treatment of metabolic diseases such as type II non-insulin dependent diabetes mellitus (NIDDM) and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. Retinoids can also be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoids include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
This invention also relates to a pharmaceutical formulation comprising one or more compounds of Formula 1 through Formula 8 or one or more of the previously known compounds disclosed below in the specification, in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal , including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids, or which are controlled by or responsive to the organism""s native retinoic acid. These formulations can also be co-administered with retinoids to enhance or prolong the effects of medications containing retinoids or of the organism""s native retinoic acid.
The present invention also relates to a method of providing a compound which is an inhibitor of the enzyme cytochrome P450RAI, wherein the method of providing the cytochrome P450RAI inhibitory compound comprises:
identifying a compound that has activity as a retinoid in any of the art recognized assays which demonstrate retinoid-like activity, the retinoid compound having a formula such that it includes a benzoic acid, benzoic acid ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or ester moiety, with a partial structure of xe2x80x94A(R2)xe2x80x94(CH2)nxe2x80x94COOR8 where the symbols are defined as in Formulas 1 through 8, and where n is 0, and
selecting a compound that is a homolog of the previously identified retinoid compound where in the formula of the homolog n is 1 or 2, preferably 1. Said homolog, if it is not a previously known compound can be prepared by homologation procedures well known to the synthetic organic chemist, such as for example the well known Arndt-Eistert synthesis. Alternatively, said homologs can be prepared by any of the applicable synthetic processes illustrated below for the preparation of the novel compounds of Formulas 1 through 8 wherein the symbol n represents the integral 1 (one).